Antihypertensive spiro(piperidine- pyrrolidine- or hexahydroazepinyl substituted) pyrrolo(2,1-c)(1,4)benzoxazepines)

ABSTRACT

This invention relates to spiro-](piperidine-, pyrrolidine-, or -hexahydroazepinyl substituted) pyrrolo[2,1-c][1,4]-benzoxazepines] having the following formula ##STR1## wherein R is hydrogen, lower alkyl, arylloweralkyl, acyl, lower alkenyl, lower alkynyl, and loweralkylbenzisoxazole; X is hydrogen, halogen, loweralkoxy, and trifluoromethyl; Y is hydrogen; 2&#39; or 3&#39; acyl, formyl, carbinol of the formula ##STR2## where R 1  and R 2  are the same or different and are independently hydrogen, loweralkyl, arylloweralkyl, aryl, loweralkenyl, lower alkynyl and lower alkylbenzisoxazole; loweralkyl, loweralkenyl and halogen; and n is an integer of 1 to 3. The compounds of this invention display utility as analgesic and antihypertensive agents.

This is a continuation of application Ser. No. 290,341 filed Dec. 29,1988, now U.S. Pat. No. 4,918,069, which is a division of applicationSer. No. 079,557 filed Jul. 30, 1987, now U.S. Pat. No. 4,812,450.

This invention relates to compounds of the formula ##STR3## wherein R ishydrogen, loweralkyl, arylloweralkyl, acyl, loweralkenyl, loweralkynyland loweralkylbenzisoxazole; X is hydrogen, halogen, loweralkoxy andtrifluoromethyl; Y is hydrogen, 2' or 3' acyl, formyl; carbinol of theformula ##STR4## where R₁ and R₂ are the same or different and areindependently hydrogen, loweralkyl, arylloweralkyl, aryl, loweralkenyl,lower alkynyl and lower alkylbenzisoxazole; loweralkyl, lower alkenyl,and halogen; and n is an integer of 1 to 3.

Throughout the specification and appended claims, a given chemicalformula or name shall encompass all geometric, optical and stereoisomersthereof where such isomers exist.

In the above definition, the term "lower" means the group it isdescribing contains from 1 to 6 carbon atoms. The term "alkyl" refers toa straight or branched chain hydrocarbon containing no unsaturation,e.g. methyl, ethyl, isopropyl, 2-butyl, neopentyl, n-hexyl, etc; theterm "arylalkyl" refers to a monovalent substituent which consists of anaryl group, e.g. phenyl, o-toluyl, m-methoxyphenyl, etc., of the formula##STR5## where Z is as defined below, linked through a loweralkylenegroup having its free valence bond from a carbon of the loweralkylenegroup, and having a formula of ##STR6## Z is hydrogen, halogen,loweralkyl, loweralkoxy, CF₃, NO₂ and NH₂ ; the term "alkylene" refersto a bivalent radical of the lower branched or unbranched alkyl group itis derived from having valence bonds from two terminal carbons thereof,e.g. ethylene (--CH₂ CH₂ --), propylene (--CH₂ CH₂ CH₂ --), isopropylene##STR7## etc; the term "alkoxy" refers to a monovalent substituent whichconsists of an alkyl group linked through an ether oxygen having itsfree valence bond from the ether oxygen, e.g. methoxy, ethoxy, propoxy,butoxy, pentoxy, etc; the term "acyl" refers to a substituent having theformula loweralkyl ##STR8## the term "alkenyl" refers to a straight orbranched chain hydrocarbon containing one unsaturated carbon to carbondouble bond, e.g. CH₂ ═CH--, CH₃ CH═CH--, ##STR9## etc.; the termalkynyl refers to a straight or branched chain hydrocarbon containingone unsaturated carbon to carbon triple bond, e.g., CH.tbd.C--, CH₃C.tbd.C--, etc.; the term loweralkylbenzisoxazole refers to asubstituent having the formula, ##STR10## where Z is hydrogen, halogen,loweralkyl, loweralkoxy, CF₃, NO₂ and NH₂ ; and the term "halogen"refers to a member of the halogen family consisting of fluorine,chlorine, bromine and iodine.

The compounds of the present invention are prepared in the followingmanner. The substituents R, X and Y are as defined above unlessindicated otherwise.

A substituted pyrrole of formula II is selected, ##STR11## where Hal isa halogen selected from Cl, Br, I. Pyrrole II is reacted under standardGrignard reagent forming conditions with magnesium in ether to form aGrignard reagent of the formula III ##STR12## which in turn is reactedunder standard Grignard conditions, such as for example in a non-polarsolvent, e.g. tetrahydrofuran, ether, etc., at a temperature of 0° C. to65° C. for 1 to 3 hours with a ketone of the formula (IV) ##STR13##tertiary alcohol having the formula ##STR14##

Alcohol (V) is reacted with a strong base, such as for example sodiumhydride, potassium t-butoxide, etc. in a polar solvent, e.g.dimethylformamide, dimethylformamide/benzene mixtures, tetrahydrofurans,etc., typically at a temperature of 25° C. to 100° C. for 1 to 6 hoursto achieve intramolecular hydrohalogen displacement to form Compound VIof the formula ##STR15## [Compound I of the invention, where Y ishydrogen].

Compound VI is reacted with N-halosuccinimide of the formula ##STR16##where Hal is a halogen selected from Cl, Br, and I, to form CompoundVIII ##STR17## This reaction is typically carried out in a suitablesolvent, such as ethereal solvent or a halogenated hydrocarbon, at atemperature of about 0°-60° C.

Compound IX of the invention, ##STR18## is formed by reacting CompoundVI with phosphorus oxychloride and dimethyl formamide. This reaction canbe conducted under conditions usually employed for carrying outVilsmeier reactions. Typically, it is conducted in a suitable solvent,such as halogenated hydrocarbon, at a temperature of 20° to 100° C.

Compound IX is subjected to a Wittig reaction with an ylide of theformula ##STR19## where R₃ and R₄ are independently hydrogen,loweralkyl, aryl, arylloweralkyl, to form ##STR20## This reaction iscarried out under conditions usually employed for carrying cut Wittigreactions. Thus, the ylide is prepared in a routine manner by firstpreparing a phosphonium salt from a bromide of the formula Br-C(R₃ R₄)Hand triphenylphosphine and thereafter reacting the phosphonium salt witha suitable base such as sodium hydride, potassium tert-butoxide orn-butyllithium in a suitable solvent such as anhydrous ethereal solvent.Thereafter a solution of Compound IX in a suitable solvent, such asanhydrous ether, is added to the freshly prepared ylide solution and themixture is stirred at a temperature of between about -10° C. and 80° C.to form Compound X.

Compound X is catalytically hydrogenated in a suitable manner known tothe art to afford a compound of formula XI, ##STR21##

Compound VI is reacted with a loweralkanoyl chloride, arylloweralkanoylchloride or aroylchloride of the formula R₅ COCl (XII), where R₅ isloweralkyl, arylloweralkyl or aryl, in the presence of zinc chloride toafford a compound of the formula XIII, ##STR22##

Compound XIII is reacted with a suitable reducing agent, e.g. NaBH₄,LiAlH₄ or borane complexes, to form compound XIV of the formula##STR23## When NaBH₄ is used, the reduction is conducted typically in alower aliphatic alcohol, such as isopropanol or ethanol, or loweralkanoic acid, at a temperature of about 0° to 80° C. After thereaction, water is added to the reaction mixture. When LiAlH₄ is used,the reduction is conducted typically in an ethereal solvent such astetrahydrofuran or ether at a temperature of about 0° to 80° C. Whenborane complexes are used, the reaction temperature is typically 0° to80° C.

Compound IX is subjected to a Grignard type reaction under conventionalGrignard conditions, such as for example in a non-polar solvent, e.g.tetrahydrofuran, ether, etc., at a temperature of 0° to 65° C. for 1 to3 hours with a Grignard reagent of the formula R₁ MgHal (XV), where Halis halogen selected from Cl, Br and I, to form a carbinol substitutedcompound of the formula ##STR24##

Compound (XIII) is subjected to a similar Grignard reaction to give acarbinol substituted compound of the formula XVI ##STR25## In apreferred embodiment R₁ and R₅ of Compound XVI (a) are lower alkyl.

In an alternative procedure, Compound I, where R is ##STR26## ishydrogenated under pressure in the presence of a noble metal catalyst,e.g. 10% Pd/C, to obtain Compound I where R is hydrogen. Typically thishydrogenation is carried out in a polar solvent, e.g. isopropanol,ethanol, etc., at a temperature of 25° C. to 50° C. for 1 to 20 hours ata pressure of 50 to 30 pounds per square inch.

Compounds of the present invention are useful as anaigesic agents due totheir ability to alleviate pain in mammals. The activity of thecompounds is demonstrated in the 2-phenyl-1,4-benzoquinone-inducedwrithing test in mice, a standard assay for analgesia [Proc. Soc. Expti.Biol. Med. 95, 729 (1957)]. The analgesic activity of some of thecompounds expressed in terms of percent inhibition of writhing are givenin TABLE I.

                  TABLE I                                                         ______________________________________                                                      Dose (subcutaneous)                                                                           Inhibition in                                   Compound      (mg/kg of body weight)                                                                        Writhing (%)                                    ______________________________________                                        1-Methyl-spiro                                                                              10.5            50                                              [piperidine-                                                                  4,11'(5H)pyrrolo                                                              [2,1-c][1,4]                                                                  benzoxazepine]                                                                Spiro[piperidine-                                                                           5.8             50                                              4,11'(5'H)pyrrolo                                                             [2,1-c][1,4]                                                                  benzoxazepine]                                                                propoxyphene (standard)                                                                     3.9             50                                              ______________________________________                                    

The analgesic relief of pain is achieved when the compounds of theinvention are administered to a subject requiring such treatment at aneffective oral, parenteral or intravenous dose of from 0.1 to 25 mg/kgof body weight per day. A preferred effective dose within this range isfrom about 1 to 10 mg/kg of body weight per day. A particularlypreferred effective amount is about 2 mg/kg of body weight per day. Itis to be understood, however, that for any particular subject, specificdosage regimens should be adjusted according to the individual need. Itis further to be understood that the dosages set forth herein areexamples only and that they do not to any extent, limit the scope ofpractice of the invention.

The compounds of the present invention are also useful asantihypertensive agents due to their ability to depress blood pressurein mammals. Antihypertensive activity is measured in the spontaneoushypertensive rat by the indirect tail cuff method described in "Methodsin Pharmacology," A. Schwartz, Ed., Vol. I, Appleton-Century Crofts, NewYork, N.Y., 1971, p. 135. In this procedure a group of five animals aretreated orally for three days with the test compound in relation to thecontrol group of the same number. The drop in blood pressure is measuredon the third day following administration. The antihypertensiveactivities of some of the compounds, expressed as mm decrease in meanarterial blood pressure are given in Table II.

                  TABLE II                                                        ______________________________________                                                          Dose (p.o.)                                                                              Decrease in                                                        mg/kg of   blood pressure                                   Compound          body weight                                                                              mm Hg                                            ______________________________________                                        1-(4-Chlorophenethyl)spiro                                                                      50         32                                               [piperidine-4,11'(5'H) pyrrolo                                                [2,1-c][1,4]benzoxazepine                                                     1-Butylspiro[piperidine-4,11'                                                                   50         23                                               (5'H)pyrrolo[2,1-c][1,4]                                                      benzoxazepine maleate                                                         1-(2-Phenethyl)spiro[piperidine-                                                                50         15                                               4,11'(5'H)pyrrolo[2,1-c][1,4]                                                 benzoxazepine                                                                 4-[1-(2-Fluorophenyl)methyl-                                                                    50         27                                               1H-pyrrol-2-yl]-1-(2-                                                         phenylethyl)-4-piperidinol                                                    2-methyl dopa (reference                                                                        50         40                                               compound)                                                                     ______________________________________                                    

Blood pressure reduction is achieved when the compounds of the inventionare administered to a subject requiring such treatment at an effectiveoral, parenteral or intravenous dose of from 0.1 to 50 mg/kg of bodyweight per day. A preferred effective dose within this range is fromabout 0.1 to 5 mg/kg of body weight per day. A particularly preferredeffective amount is about 1 mg/kg of body weight per day. It is to beunderstood, however, that for any particular subject, specific dosageregimens should be adjusted according to the individual need and theprofessional judgment of the person administering or supervising theadministration of the compounds of the invention. It is to be furtherunderstood that the dosages set forth herein are examples only and thatthey do not, to any extent, limit the scope or practice of theinvention.

The compounds of the present invention may be administered orally, forexample, with an inert diluent or with an edible carrier. They may beenclosed in gelatin capsules or compressed into tablets. For the purposeof oral therapeutic administration, the compounds may be incorporatedwith excipients and used in the form of tablets, troches, capsules,elixirs, suspensions, syrups, wafers, chewing gums and the like. Thesepreparations should contain at least 4% spiro[piperidine-, pyrrolidine-,or hexahydroazepinyl substituted- pyrrolo [2,1-c][1,4]benzoxazepines] ofthe invention, the active ingredient, but may be varied depending uponthe particular form and may conveniently be between 4% to about 70% ofthe weight of the unit. The amount of the compound present in suchcompositions is such that a suitable dosage will be obtained. Preferredcompositions and preparations according to the present invention areprepared so that an oral dosage unit form contains between 5.0-300milligrams of the spiro[piperidine-, pyrrolidine-, or hexahydroazepinylsubstituted pyrrolo[2,1-c][1,4]benzoxazepines] of the present invention.

The tablets, pills, capsules, troches and the like may also contain thefollowing adjuvants: a binder such as microcrystalline cellulose, gumtragacanth or gelatin; an excipient such as starch or lactose, adisintegrating agent such as alginic acid, Primogel, corn starch and thelike; a lubricant such as magnesium stearate or Sterotex; a glidant suchas colloidal silicon dioxide; and a sweetening agent such as sucrose orsaccharin may be added or a flavoring agent such as peppermint, methylsalicylate or orange flavoring. When the dosage unit form is a capsule,it may contain, in addition to material of the above type, a liquidcarrier such as a fatty oil. Other dosage unit forms may contain othervarious materials which modify the physical form of the dosage unit, forexample, as coatings. Thus, tablets or pills may be coated with sugar,shellac, or other enteric coating agents. A syrup may contain, inaddition to the present compounds, sucrose as a sweetening agent andcertain preservatives, dyes and colorings and flavors. Materials used inpreparing these various compositions should be pharmaceutically pure andnon-toxic in the amounts used.

For the purpose of parenteral therapeutic administration, the compoundsof the present invention may be incorporated into a solution orsuspension. These preparations should contain at least 0.1% of thespiro[piperidine-, pyrrolidine- or hexahydroazepinyl substituted-pyrrolo[2,1-c][1,4]benzoxazepine] derivative of the invention, but maybe varied to be between 0.1 and about 50% of the weight thereof. Theamount of the inventive compound present in such compositions is suchthat a suitable dosage will be obtained. Preferred compositions andpreparations according to the present invention are prepared so that aparenteral dosage unit contains between 5.0 to 100 milligrams of thespiro[piperidine-, pyrrolidine- or hexahydroazepinyl substituted-pyrrolo[2,1-c][1,4]benzoxazepine] derivative of the invention.

The solutions or suspensions may also include the following adjuvants: asterile diluent such as water for injection, saline solution, fixedoils, polyethylene glycols, glycerine, propylene glycol or othersynthetic solvents; antibacterial agents such as benzyl alcohol ormethyl paraben; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylene diaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parenteral preparationcan be enclosed in ampules, disposable syringes or multiple dose vialsmade of glass or plastic.

Examples of some of the compounds include:

1-acetylspiro[piperidine-4,11'(5'H)-pyrrolo[2,1-c][1,4]benzoxazepine];

1-oxobutylspiro[piperidine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

1-(3-butenyl)spiro[piperidine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

1-(3-methyl-2-butenyl)spiro[piperidine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

1-(2-propynyl)spiro[piperidine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

1-cyclopropylmethylspiro[piperidine-4,11(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

6'-fluorospiro[piperidine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

8'-chlorospiro[piperidine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

8'-(1-ethyl-propoxy)spiro[piperidine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

8'-trifluoromethylspiro[piperidine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

1-(2-methyl-oxopropyl)spiro[piperidine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

3'-formylspiro[piperidine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

2'-pentylspiro[piperidine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

3'-bromospiro[piperidine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

3'-(1-butenyl)spiro[piperidine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

2'-(1-propenyl)spiro[piperidine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine]

7'-fluoro-1-propylspiro[piperidine-4,11'(5H)pyrrolo[2,1-c][1,4]benzoxazepine];

7'-ethoxy-1-(4,4-diphenylbutyl)spiro[piperidine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

1-acetyl-6'-trifluoromethylspiro[piperidine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

9'-chloro-1-(2-propenyl)spiro[piperidine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

6'-methoxy-1-(2-propynyl)spiro[piperidine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

3'-acetyl-1-methylspiro[piperidine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

3'-formyl-1-phenbutylspiro[piperidine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

3'-oxopropyl-1-[(3-methyl)butyl]spiro[piperdine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

1-ethyl-3'ethenylspiro[piperidine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

2'-iodo-1-methylspiro[piperidine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

3'-acetyl-8'-fluorospiro[piperidine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

3'-formyl-6'-methoxy-1-methylspiro[piperidine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

3'-propyl-9'-trifluoromethylspiro[piperidine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

7'-chloro-2'-(1-propenyl)spiro[piperidine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

3'-bromo-6'-chlorospiro[piperidine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

3'-acetyl-9'-fluoro-1-methylspiro[piperidine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

8'-chloro-2'-formyl-1-phenylmethylspiro[piperidine-4,11(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

1-acetyl-8'-methoxy-3'-propylspiro[piperidine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

3'-ethenyl-1-(2-propenyl)-6'-trifluoromethylspiro[piperidine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

8'-butoxy-2'-iodo-1-(butyl)spiro[piperidine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

1-methyl-spiro[pyrrolidine-3,11'(5'H)pyrrolo[2,1c][1,4]benzoxazepine];

spiro[pyrrolidine-3,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

1-benzyl-spiro[pyrrolidine-3,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

1-phenylethyl-spiro[pyrrolidine-3,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

3'-chloro-1-methyl-spiro[pyrrolidine-3,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

3'-chloro-spiro[pyrrolidine-3,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

3'-chloro-8'-fluoro-1-methyl-spiro[pyrrolidine-3,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

8'-fluoro-spiro[pyrrolidine-3,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

1-benzyl-7'-methoxy-spiro[pyrrolidine-3,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

methyl-spiro[2,3,4,5,6,7-hexahydro-1H-azepine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

spiro[2,3,4,5,6,7-hexahydro-1H-azepine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

1-benzyl-spiro[2,3,4,5,6,7-hexahydro-1H-azepine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

1-phenylethyl-spiro[2,3,4,5,6,7-hexahydro-1H-azepine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

3'-chloro-1-methyl-spiro[2,3,4,5,6,7-hexahydro-1H-azepine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

3'-bromo-spiro[2,3,4,5,6,7-hexahydro-1H-azepine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

3'-chloro-8'-fluoro-1-phenylethyl-spiro[2,3,4,5,6,7-hexahydro-1H-azepine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine];

8'-fluoro-spiro[2,3,4,5,6,7-hexahydro-1H-azepine-4,11'(5'H)pyrrolo[2,1-c[1,4]benzoxazepine];

The following examples are for illustrative purposes and are not to beconstrued as limiting the invention disclosed herein. All temperaturesare given in degrees centigrade.

EXAMPLE 1 a.4-[1-(2-Fluorophenyl)methyl-1H-pyrrol-2-yl]-1-(2-phenylethyl)-4-piperidinol

A solution of 2-bromo-1-[(2-fluorophenyl)methyl]pyrrole (11.18 g; 0.044moles in 30 ml tetrahydrofuran [THF]) was added to a suspension ofmagnesium turnings (1.17 g; 0.048 moles in 40 ml 10% ether/THF). Thereaction mixture was initiated with a few drops of 1,2-dibromoethane andheat and was then refluxed for 30 minutes. To this mixture was added asolution of 1-(2-phenylethyl)-4-piperidone (7.73 g; 0.038 moles in 40 mlTHF). The reaction was then refluxed for 45 minutes. The reaction wasquenched into iced NH₄ Cl solution and this was extracted thrice withethyl acetate. The combined organics were washed once with water anddried (saturated NaCl solution, anhydrous MgSO₄). The solution wasfiltered and concentrated to a semi-solid product which was thenpurified via high pressure liquid chromatography (HPLC)[THF:dichloromethane:diethylamine/10:90:0.5] to give 7.26 g (50%) of asolid, m.p. 125°-129° C. The solid was recrystallized from isopropylether to give4-[1-(2-fluorophenyl)methyl-1H-pyrrol-2-yl]-1-(2-phenylethyl)-4-piperidinol,m.p. 130°-131° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.24 H.sub.27 FN.sub.2 O:                                                   76.16% C 7.19% H   7.40% N                                   Found:           76.02% C 7.23% H   7.37% N                                   ______________________________________                                    

b.1-(2-Phenylethyl)spiro[piperidine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazapine]

To a suspension of NaH (0.66 g; 0.014 moles 50% in oil, treated withhexane) in 15 ml 20% dimethylformamide (DMF)/benzene was added asolution of4-[1-(2-fluorophenyl)methyl-1H-pyrrol-2-yl]-1-(2-phenylethyl)-4-piperidinolof Example 1a. (4.33 g; 0.011 moles in 85 ml 20% DMF/benzene). This washeated at 70° C. for 3.5 hours. The reaction was then quenched into icedH₂ O and extracted thrice with ethyl acetate. The combined organics werewashed once with H₂ O and dried (saturated NaCl solution, anhydrousMgSO₄). The resultant solution was filtered and concentrated to an oilwhich was purified via HPLC (2% methanol/dichloromethane) to yield 3.26g (83%) of a solid, m.p.: slight melt at 70°-73° C., 150°-152° C. Thesolid was recrystallized from isopropyl ether to give1-(2-phenylethyl)spiro[piperidine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine], m.p. initial: 73.5°-75° C., final, 150°-152° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.24 H.sub.26 N.sub.2 O:                                                   80.41% C  7.31% H   7.81% N                                   Found:          80.25% C  7.35% H   7.69% N                                   ______________________________________                                    

EXAMPLE 2 a.4-[1-(2-Fluorophenyl)methyl-1H-pyrrol-2-yl]-1-methyl-4-piperidinol

A solution of 2-bromo-1-[(2-fluorophenyl)methyl]pyrrole (11.9 g; 0.047moles in 25 ml THF) was added to a suspension of magnesium turnings (1.3g; 0.05 moles in 20 ml THF/5 ml ether). The reaction was initiated witha few drops of 1,2-dibromoethane and a reflux was maintained by additionof the pyrrole. After the reflux subsided, the reaction was cooled toice bath temperature. To this was added a solution of1-methyl-4-piperidone (3.5 g; 0.03 moles in 15 ml THF). The reaction wasstirred for 20 minutes and quenched into iced NH₄ Cl solution. This wasextracted twice with ethyl acetate and the combined organics were washedonce with H₂ O and dried (saturated NaCl solution, anhydrous MgSO₄). Theresultant solution was filtered and concentrated to give a semi-solid.Trituration of this material with hexane yielded 3.22 g (36%) of asolid, m.p. 159°-162° C. This solid was recrystallized from isopropylether to give4-[1-(2-fluorophenyl)methyl-1H-pyrrol-2-yl]-1-methyl-4-piperidinol, m.p.164°-165° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.17 H.sub.21 FN.sub.2 O:                                                   70.81% C 7.34% H  9.71% H                                    Found:           70.64% C 7.41% H  9.56% H                                    ______________________________________                                    

b. 1-Methylspiro[piperidine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine

To a suspension of sodium hydride (0.7 g; 0.014 moles, 50% in oil,treated with hexane) in 30 ml 20% DMF/benzene was added a solution of4-[1-(2-fluorophenyl)methyl-1H-pyrrol-2-yl]-1-methyl-4-piperidinol ofExample 2a, (3.2 g; 0.011 moles) in 30 ml 20% DMF/benzene. This washeated at 70° C. oil bath temperature for four hours. The reaction wasthen quenched into dilute NaCl solution and extracted twice with diethylether. The combined organics were washed once with H₂ O and dried(saturated NaCl solution, anhydrous MgSO₄). This was filtered andconcentrated to give a semi-solid. This solid was purified via HPLC (3%methanol/dichloromethane) to yield 1.85 g (63%) of a solid, m.p.94°-100° C. The solid was recrystallized from isopropyl ether to give1-methyl-spiro[piperidine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine],m.p. 100°-101° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.17 H.sub.20 N.sub.2 O:                                                   76.09% C 7.51% H   10.44% N                                   Found:          75.84% C 7.45% H   10.30% N                                   ______________________________________                                    

EXAMPLE 3 a.1-(4-Chlorophenethyl)-4-[1-(2-fluorobenzyl)pyrrol-2-yl]4-piperidinol

To a suspension of magnesium turnings (1.0 g, 0.04 mole) in 25 mltetrahydrofuran (THF) and 10 ml ether, was added a few drops of asolution of 2-bromo-1-(2-fluorobenzyl)pyrrole (10.0 g, 0.04 mole) in 30ml THF. The reaction was initiated with a few drops of dibromoethane andheat, and reflux was maintained by the addition of the bromo compoundafter stirring at reflux for 30 minutes, the mixture was cooled with anice-bath; then a solution of 1-(4-chlorophenethyl)-4-piperidone (5.0 g,0.021 mole) was added. After stirring at ambient temperature for onehour, the mixture was poured into a solution of NH₄ Cl, then extractedwith ether. The ether solution was washed with water, then dried overanhydrous MgSO₄. After evaporation of the solvent, the resultant oil, 12g, was purified by high pressure liquid chromatography (HPLC), usingethyl acetate as the eluent to give 4.5 g of1-(4-chlorophenethyl)-4-[1-(2-fluorobenzyl)pyrrol- 2-yl]-4-piperidinol,m.p. 108°-9° C.

b. 1-(4-Chlorophenethyl)spiro[piperidine-4,11'(5'H) pyrrolo[2,1-c][1,4]benzoxazepine]

To a suspension of NaH (50% in oil, washed with hexanes, 0.62 g, 0.013mole) in 20 ml benzene, was added a solution of1-(4-chlorophenethyl)-4-[1-(2-fluorobenzyl)pyrrol-2-yl]-4-piperidinol(4.0 g, 0.01 mole) of Example 3a in 50 ml benzene and 30 ml DMF. Afterstirring at 90° C. for two hours, the mixture was poured into 200 mlwater and stirred for five minutes, then extracted with ethylacetate/ether. The organic layer was washed twice with water, then dried(saturated NaCl, anhydrous MgSO₄). After filtering, the solvents wereevaporated to a solid, 3.6 g, m.p. 105°-108° C., which wasrecrystallized from isopropyl ether to yield 3.0 g (75%) of product,m.p. 114°-5° C. This material was recrystallized from isopropyl ether togive 2.5 g of1-(4-chlorophenethyl)spiro[piperidine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine],m.p. 116°-8° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.24 H.sub.25 ClN.sub.2 O:                                                   73.36% C 6.41% H  7.13% N                                   Found:            73.28% C 6.54% H  6.96% N                                   ______________________________________                                    

EXAMPLE 4 a.4-[1-(2-Fluorophenyl)methyl-1H-pyrrol-2-yl]-1-benzyl-4-piperidinol

To a suspension of magnesium turnings (2.2 g, 0.09 mole) in 60 mltetrahydrofuran (THF) and 30 ml ether, was added a few drops of asolution of 2-bromo-1-(2-fluorobenzyl)pyrrole (20 g, 0.074 mole) in 60ml THF. The reaction was initiated with a few drops of dibromoethane andheat, and reflux was maintained by the addition of the bromo compound.After stirring at reflux for 30 minutes, the mixture was cooled with anice bath, then a solution of 1-benzyl-4-piperidone (11.2 g, 0.06 mole)in 75 ml THF was added. After stirring at ambient temperature for onehour, the mixture was poured into NH₄ Cl solution, then extracted withethyl acetate. The ethyl acetate solution was washed with water, thendried over anhydrous MgSO₄. After evaporation of the solvent, theresultant oil (25 g) was purified by HPLC, using ethylacetate/hexane/diethylamine (30:70:0.5) as the eluent to give 15.8 g of4-[1-((2-fluorophenyl)methyl)- 1H-pyrrol-2-yl]-1-benzyl-4-piperidinol,m.p. 112°-117° C.

b. 1-Benzylspiro[piperidine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine]

To a suspension of sodium hydride (2.55 g; 0.052 moles; 50% in oil,treated with hexane) in 30 ml 30% DMF/benzene was added a solution of4-[1-(2-fluorophenyl)methyl-1H-pyrrol-2-yl]-1-benzyl-4-piperidinol (14.5g; 0.014 moles) in 120 ml 30% DMF/benzene of Example 4a. This mixturewas heated at 75° C. for 4.5 hours. The mixture was quenched into icedH₂ O and extracted twice with ethyl acetate. The combined organics werewashed twice with H₂ O and dried (saturated NaCl solution, anhydrousMgSO₄). This was filtered and concentrated to an oil. The amine productwas crystallized out by treating the oil with isopropyl ether to give8.55 g (61%) of a solid, m.p. 105°-109° C. This solid was twicerecrystallized from isopropyl ether to give1-benzylspiro[piperidine-4,11'(5' H)pyrrolo[2,1-c][1,4]benzoxazepine],m.p. 109°-111° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.23 H.sub.24 N.sub.2 O:                                                   80.20% C  7.02% H  8.13% N                                    Found:          80.59% C  7.06% H  7.56% N                                    ______________________________________                                    

EXAMPLE 5Spiro[piperidine-4,11'(5'H)pyrrolo[2,1-c]1,4]benzoxazepine]maleate

A suspension of1-benzylspiro[piperidine-4,11'-(5'H)pyrrolo[2,1-c][1,4]benzoxazepine](4.8 g; 0.014 moles) of Example 4b and 1.5 g 10% Pd/C in 150 mlisopropanol in a Parr hydrogenation apparatus, was pressurized to 50 psiwith hydrogen and heated to 50° C. The mixture was shaken for eighthours and let stand under hydrogen overnight. The catalyst was thenfiltered and the solution concentrated to give an oil. The resultantamine was purified via HPLC (THF:diethylamine; 100:1) to yield 2.9 g(81%) of a semi-solid. The maleate salt of the amine was formed viaaddition of a maleic acid/diethyl ether solution to give 3.05 g of asolid, m.p. 167°-170° C. The solid was recrystallized three times fromisopropanol/diethyl ether (1:2) to givespiro[piperidine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine]. m.p.168°-170° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for                                                                C.sub.16 H.sub.18 N.sub.2 O.C.sub.4 H.sub.4 O.sub.4 :                                       64.85% C   5.99% H  7.56% N                                     Found:        64.70% C   6.21% H  7.47% N                                     ______________________________________                                    

EXAMPLE 6 a. 1-Butyl-4-[1-(2-fluorobenzyl)pyrrol-2-yl]-4-piperidinol

To a suspension of magnesium turnings (1.0 g, 0.04 mole) in 25 mltetrahydrofuran (THF) and 10 ml ether, was added a few drops of asolution of 2-bromo-1-(2-fluorobenzyl)pyrrole (10 g, 0.04 mole) in 35 mlTHF. The reaction was initiated with a few drops of dibromoethane andheat, and reflux was maintained by the addition of the bromo compound.After stirring at reflux for thirty minutes, the mixture was cooled withan ice-bath, then a solution of 1-butyl-4-piperidone (4.6 g, 0.03 mole)in 25 ml THF was added. After stirring at ambient temperature for onehour, the mixture was poured into an NH₄ Cl solution, then extractedwith ether. The ether solution was washed with water, then dried overanhydrous MgSO₄. After evaporation of the solvent, the resultant oil (11g) was purified by HPLC using ethyl acetate as the eluent to give 3.4 gof 1-butyl-4-[1-(2-fluorobenzyl)pyrrol-2-yl]-4-piperidinol; m.p. 132°-5°C.

b.l-Butylspiro[piperidine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine]maleate

To a suspension of NaH (50% in oil, washed with hexanes, 0.62 g, 0.013mole) in 20 ml benzene, was added a solution of1-butyl-4-[1-(2-fluorobenzyl)pyrrol-2-yl]-4-piperidinol (3.2 g, 0.01mole) of Example 6a in 50 ml benzene and 30 ml DMF. After stirring at90° C. for seven hours, the mixture was poured into 200 ml water,stirred for five minutes, then extracted with ether. The organic layerwas washed twice with water, then dried (saturated NaCl, anhydrousMgSO₄). After filtering, the solvents were evaporated to an oil, (3 g),which was dissolved in ether, then acidified to pH 1 with etherealmaleic acid. The resultant precipitate was collected and dried to yield2.7 g (64%) of product, m.p. 163°-166° C. This compound wasrecrystallized twice from isopropanol/ether (1:10) to yield1-butyl-spiro[piperidine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine]maleate, m.p.175°-7° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for                                                                C.sub.20 H.sub.26 N.sub.2 O.C.sub.4 H.sub.4 O.sub.4 :                                       67.58% C   7.09% H  6.57% N                                     Found:        67.40% C   7.00% H  6.55% N                                     ______________________________________                                    

EXAMPLE 7 a.1-[3-(6-Fluoro-1,2-benzisoxazol-3-yl)propyl]-4-[1-(2-fluorobenzyl)pyrrol-2-yl]-4-piperidinol

To a suspension of magnesium turnings (1.0 g, 0.04 mole) in 25 mltetrahydrofuran (THF) and 10 ml ether, was added a few drops of asolution of 2-bromo-1-(2-fluorobenzyl)pyrrole (10 g, 0.04 mole) in 30 mlTHF. The reaction was initiated with a few drops of dibromoethane andheat, and reflux was maintained by the addition of the bromo compound.After stirring at reflux for 30 minutes, the mixture was cooled; then asolution of 1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-piperidone(5.2 g, 0.019 mole) in 50 ml THF was added. After stirring at ambienttemperature for one hour, the mixture was poured into an NH₄ Clsolution, then extracted with ether. The ether layer was washed withwater, then dried over anhydrous MgSO₄. After evaporation of thesolvent, the resultant oil (13 g), was purified by HPLC using ethylacetate with 0.5% Diethylamine as the eluent to give 6.2 g of1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-[1-(2-fluorobenzyl)propyl-2-yl]-4-piperidinol,m.p. 100°-4° C.

b.1-[3-(6-Fluoro-1,2-benzisoxazol-3-yl)propyl]spiro[piperidine-4,11'(5'H)-pyrrolo[2,1-c][1,4]benzoxazepine]maleate

To 80 ml benzene and 20 ml DMF was added sodium hydride (0.72 g, 0.015mole, 50% in oil, treated with hexanes) and1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-[1-(2-fluorobenzyl)pyrrol-2-yl]-4-piperidinol(5.2 g, 0.012 mole) of Example 7a. After stirring at 80° C. for fivehours, the mixture was poured into 500 ml water, stirred for fiveminutes, then extracted with ether/ethyl acetate. The organic layer wascollected, washed twice with water, then dried (saturated NaCl,anhydrous MgSO₄). After filtering, the solvents were evaporated to anoil, which was dissolved in ether, then acidified to pH 1 withethereal-maleic acid. The resultant precipitate was collected and driedto yield 5.5 (84%), of product, m.p. 155° C. This compound wasrecrystallized twice from isopropanol/methanol/ether (5:1:5) to yield1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]spiro[piperidine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine]maleate, m.p. 163°-165° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for                                                                C.sub.26 H.sub.26 FN.sub.3 O.sub.2.C.sub.4 H.sub.4 O.sub.4 :                                 65.80% C  5.52% H   7.67% N                                    Found:         66.20% C  5.79% H   7.72% N                                    ______________________________________                                    

We claim:
 1. An antihypertensive composition which comprises aneffective blood pressure reducing amount of a compound of the formula##STR27## wherein R is hydrogen, loweralkyl, arylloweralkyl, acyl,loweralkenyl, loweralkynyl, and ##STR28## where Z is hydrogen, halogen,loweralkyl, loweralkoxy, CF₃, NO₂ and NH₂ ; X is hydrogen, halogen,loweralkoxy and trifluoromethyl; Y is hydrogen, 2' or 3' acyl, formyl,carbinol of the formula ##STR29## where R₁ and R₂ are the same ordifferent and are independently hydrogen, loweralkyl, arylloweralkyl,aryl, lower alkenyl, lower alkynyl and lower alkylbenzisoxazole;loweralkyl, loweralkenyl and halogen; and n is an integer of from 1 to 3and the pharmaceutically acceptable acid addition salts thereof andwhere applicable the geometric and stereo isomers thereof; and asuitable carrier therefor.
 2. The composition as defined in claim 1wherein n is
 1. 3. The composition as defined in claim 1 wherein n is 2.4. The composition as defined in claim 1 which comprises1-(2-phenylethyl)spiro[piperidine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine] and thepharmaceutically acceptable addition salts thereof.
 5. The compositionas defined in claim 1 which comprises which comprises1-methylspiro[piperidine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine] andthe pharmaceutically acceptable addition salts thereof.
 6. Thecomposition as defined in claim 1 which comprises1-(4-chlorophenethyl)spiro[piperidine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine] and the pharmaceutically acceptableaddition salts thereof.
 7. The composition as defined in claim 1 whichcomprises 1-benzylspiro[piperidine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine] and the pharmaceutically acceptableaddition salts thereof.
 8. The composition as defined in claim 1 whichcomprises spiro[piperidine-4,11'(5'H) pyrrolo[2,1-c][1,4]benzoxazepine]and the pharmaceutically acceptable addition salts thereof.
 9. Thecomposition as defined in claim 1 which comprises1-butylspiro[piperidine-4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine] andthe pharmaceutically acceptable addition salts thereof.
 10. Thecomposition as defined in claim 1 which comprises1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]spiro[piperidine4,11'(5'H)pyrrolo[2,1-c][1,4]benzoxazepine] and the pharmaceutically acceptableaddition salts thereof.